Acebrophylline is a mucolytic bronchodilator used for the treatment of Chronic Obstructive Pulmonary Disorders (COPD). Acebrophylline act like an airway mucus regulator with Anti-inflammatory action. A number of processes are known for preparing Acebrophylline.
DE3425007 describes preparation of Acebrophylline involving reaction of ambroxol base and theophylline-7-acetic acid in a polar aprotic solvent followed by precipitation using ethyl acetate.
However, this process is disadvantageous and not suitable for large scale commercial preparation as it requires very high volume of ethyl acetate for precipitation and separation. The yield obtained by this method is only 85% of the theoretical yield.
BR2001003368 describes preparation of Acebrophylline by neutralization of methanolic solutions of ambroxol base and theophylline-7-acetic acid in the presence of activated carbon and alumina during reflux.
The use and handling of alumina in bulk at the production level is problematic. Further, the product separation has to be achieved by adding ethanol; followed by removing mixture of methanol and ethanol by distillation.
CN101407517B describes preparation of Acebrophylline employing theophylline-7-acetic acid and ambroxol base in 1:1.49-1.69 weight proportion using mixture of water with ethanol or ethanol as a solvent.
The process uses excess of ambroxol base which is not commercially feasible. Also, the yield of crude product obtained is only 77% of the theoretical yield and the crude product needs to be re-crystallized. Further, isolation of the product is effected by the distillation followed by filtration.
The processes for the preparation of Acebrophylline known in the art suffers from several drawbacks like, lower yields, use of higher amount of reactants, higher volume of solvents, longer reaction time and cumbersome product isolation procedures. Therefore, improved methods for the industrial scale preparation of Acebrophylline are desirable which can overcome the above mentioned drawbacks.